Obesity has increased dramatically over the past 30 years in the US and is associated with increased mortality rates of various cancers, including prostate cancer (PCa). Insights into the mechanism(s) underiying the enhanced progression of PCa associated with obesity are urgently needed to develop new strategies for preventing and treating obesity related PCa. Recently, we have reported that obesity has a significant role in PCa progression for patients with localized disease independent of treatment (prostatectomy or radiation. Body mass index (BMI) appears to be an independent risk factor for either biochemical failure (BF) or clinical failure (CF) and our new data suggest that fat intake modulates tumor progression. In animal studies, we have recently found that positive (obese diet) and negative (calorie- restricted diet) energy balance modulate activity of the Akt/mTOR signaling pathway in several mouse tissues including the prostate. Finally, preliminary studies have shown enhanced progression of PCa in HiMyc transgenic mice maintained on an obesity-inducing high fat diet. Our data also suggest that enhanced signaling through Akt and mTOR may play a role in this enhanced progression associated with maintenance on an obesity-inducing diet. Taken together, these findings suggest that pathways activated by obesity, such as the Akt/mTOR pathways, may be key targets for preventing and controlling obesity-related PCa progression. In this project, we propose to use the well-characterized HiMyc mouse prostate tumor model, in combination with dietary and pharmacologic approaches, to test this hypothesis. Additionally, we will evaluate the relevance of changes in these signaling pathways (including both upstream and downstream components) using serum, germline DNA and tumor tissue from PCa patients who are part of ongoing studies at the UT MD Anderson Cancer Center. Findings from these proposed studies will provide the basis for future translational studies targeting specific pathways via lifestyle and pharmacologic approaches to reduce PCa specific mortality. The hypothesis to be tested in this proposal is that diet-induced obesity and/or high fat diet impacts PCa progression through modulation of Akt, mTOR and their downstream signaling pathways. The specific aims are 1) To establish the impact and underiying mechanisms of enhanced PCa progression in HiMyc mice due to diet-induced obesity, 2) To characterize pharmacologic interventions that offset the increased risk of PCa progression associated with diet-induced obesity (DIO)/ high fat (HF) diet in HiMyc mice, and 3) To extend the dietary and intervention associations with PCa progression identified in Specific Aims 1 and 2 to two well-characterized populations of PCa patients. RELEVANCE (See Instructions): In this project, we propose to use the well-characterized HiMyc mouse prostate tumor model, in combination with dietary and pharmacologic approaches, to test the hypothesis that diet-induced obesity and/or high fat diet impacts PCa progression through modulation of Akt, mTOR and their downstream signaling pathways. Additionally, we will evaluate the relevance of changes in these signaling pathways (including both upstream and downstream components) using serum, germline DNA and tumor tissue from PCa patients who are part of ongoing studies at the UT MD Anderson Cancer Center. Findings from these proposed studies will provide the basis for future translational studies targeting specific pathways via lifestyle and pharmacologic approaches to reduce PCa specific mortality.